A Phase 1, First-in-Human Study of CUSP06, a Cadherin-6 (CDH6)-directed Antibody-Drug Conjugate, in Patients with Platinum-Refractory/Resistant Ovarian Cancer and Other Advanced Solid Tumors
Trial Description
This phase 1 study will evaluate the safety, tolerability, pharmacokinetics, and efficacy
of CUSP06 in patients with platinum-refractory/resistant ovarian cancer and other
advanced solid tumors.
Eligibility Requirements
Inclusion Criteria:
- Written informed consent provided prior to any screening procedures.
- Male or female patients, ≥18 years of age at the time of obtaining informed consent.
- Patients with histologically or cytologically confirmed advanced solid tumors
previously treated with standard of care systemic therapy, or for whom no standard
therapy is available.
- Willingness to provide archival tumor tissue collected within the previous 2 years,
when available. If no archival tissue is available that was collected within a 2
year timeframe, willingness to undergo a pretreatment biopsy if medically feasible
and safe.
- For patients on Phase 1b dose expansion, willingness to undergo pre- and
on-treatment biopsies if medically feasible and safe.
- Measurable disease per RECIST 1.1.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and life
expectancy of ≥12 weeks.
- Adequate organ function as defined by:
- Absolute neutrophil count (ANC) ≥1.5 x 109/L (1500/µL), without
colony-stimulating factor support for the past 14 days.
- Platelets ≥100.0 x 109/L (100 000/µL).
- Hemoglobin ≥9.0 g/dL (without blood transfusion in 2-week period prior to
screening laboratory tests).
- Creatinine clearance (CrCl) ≥45 mL/min as calculated by the Cockcroft-Gault
method.
- Serum total bilirubin ≤ 1.5 x the upper limit of normal (ULN).
- Aspartate aminotransferase (AST) ≤2.5 x ULN; alanine aminotransferase (ALT) ≤
2.5 x ULN.
- International normalized ratio (INR) ≤ 1.5; activated partial thromboplastin
time (aPTT) ≤ 1.5 x ULN.
- Left ventricular ejection fraction (LVEF) ≥50% as per echocardiography (ECHO)
or multi-gated acquisition scan (MUGA).
- Q wave to T wave (QT) interval corrected for heart rate (QTc) ≤480 ms
(Fridericia's formula).
- Women of child-bearing potential (WCBP), defined as a sexually mature woman who has
not undergone surgical sterilization or who has not been naturally postmenopausal
for at least 12 consecutive months (i.e., who has had menses any time in the
preceding 12 consecutive months) must agree to use 2 effective contraceptive
methods; examples include oral, parenteral, or implantable hormonal contraceptive,
intra-uterine device, barrier contraceptive with spermicide, partner's latex (or
polyisoprene, if latex allergy) condom or vasectomy while on study treatment and for
at least 12 weeks after the last dose of the study drug.
- WCBP must have a negative serum pregnancy test within 72 hours prior to first
dose of the study drug.
- Male patients must agree to use a latex (or polyisoprene, if latex allergy)
condom, even if they had a successful vasectomy, while on study treatment and
for at least 12 weeks after the last dose of the study drug.
- Patients must be willing and able to sign the informed consent form, and to adhere
to the study visit schedule and other protocol requirements.
Exclusion Criteria:
- Prior treatment an ADC with a topoisomerase I (TOP1) payload.
- Active or progressing brain metastases or evidence of leptomeningeal disease.
Stable/treated brain metastases are permitted (defined as history of brain
metastases previously treated with surgical resection or stereotactic radiosurgery,
stable on baseline screening study MRI brain for at least 2 months (compared to
comparator MRI brain) and asymptomatic without requirement for steroids or
antiseizure medications.
- Persistent toxicities from previous systemic antineoplastic treatments of Grade >1,
excluding alopecia and vitiligo.
- Systemic antineoplastic therapy within 5 half-lives or 4 weeks, whichever is
shorter, prior to first dose of the study drug, including investigational agents.
- Wide-field radiotherapy (e.g., >30% of marrow-bearing bones) within 4 weeks, or
focal radiation with palliative intent outside the field of measurable disease
within 2 weeks prior to first dose of the study drug.
- Major surgery (not including placement of vascular access device or tumor biopsies)
within 4 weeks prior to first dose of study drug, or no recovery from side effects
of such intervention.
- Has had clinically significant lung disease requiring systemic corticosteroid
treatment within the last 6 months of randomization/registration (e.g., interstitial
pneumonia, pneumonitis, pulmonary fibrosis, and severe radiation pneumonitis) or who
are suspected to have such diseases by imaging at screening period.
- Patients with acute or chronic pancreatitis and/or any cirrhosis except cirrhosis
diagnosed as Child-Pugh class A.
- Hepatic insufficiency manifesting as clinical jaundice, hepatic encephalopathy,
and/or variceal bleed within 60 days prior to study entry.
- History of liver transplant.
- Prior allogeneic bone marrow transplantation.
- Significant cardiac disease, such as recent (within 6 months prior to first dose of
the study drug) myocardial infarction or acute coronary syndromes (including
unstable angina pectoris), congestive heart failure (New York Heart Association
class III or IV), uncontrolled hypertension, uncontrolled cardiac arrhythmias,
severe aortic stenosis.
- History of thromboembolic or cerebrovascular events, including transient ischemic
attacks, cerebrovascular accidents, deep vein thrombosis, or pulmonary emboli within
3 months prior to first dose of the study drug.
- Acute and/or clinically significant bacterial, fungal, or viral infection including
hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV).
- Note: patients with chronic HBV, HCV or HIV infection will be eligible if they
are considered upon a mutual agreement of the Investigator and the Medical
Monitor as safe for enrollment and meet one of the following additional
conditions:
- Patients with HIV infection are on an established antiretroviral therapy for at
least 4 weeks, and have CD4+ T-cell counts ≥350 cells/µL and HIV viral load
<400 copies/mL,
- Patients with serologic evidence of chronic HBV infection receive concurrent
anti-HBV therapy and have HBV viral load below the limit of quantification,
- Patients with a history of HCV infection must have completed curative anti-HCV
therapy and have HCV viral load below the limit of quantification,
- Patients on concurrent anti-HCV therapy have HCV viral load below the limit of
quantification.
- Known or suspected allergy to the study drug or any component of the study drug.
- Concurrent participation in another investigational clinical trial.
- Pregnant or breast-feeding females.
- Prior history of malignancy other than inclusion diagnosis within 3 years prior to
first dose of the study drug.
- Note: patients with adequately treated basal cell or squamous cell skin cancer,
non-invasive superficial bladder cancer, in situ cervical cancer, in situ
breast cancer, in situ prostate cancer may be eligible if have shown no
evidence of active disease for 2 years prior to first dose of drug.
- Any other severe acute or chronic medical or psychiatric conditions or laboratory
abnormality that may increase the risk associated with the study participation or
the study drug administration or may interfere with the interpretation of study
results and, in the judgment of the Investigator, would make the patient
inappropriate for enrollment in this study.